Dietary Modulation of Neuroinflammation in Age-Related Memory Disorders

饮食调节与年龄相关的记忆障碍中的神经炎症

基本信息

批准号：
9975668
负责人：
Richard P SLOAN
金额：
$ 76.41万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-01 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9975668
关键词：
Active Biological Transport Age Age-Related Memory Disorders Age-associated memory impairment Aging Alzheimer&apos s Disease Amyotrophic Lateral Sclerosis Antioxidants Binding Blood Blood - brain barrier anatomy Blood Platelets Blood Pressure Brain Brain region Cells Clinical Clinical Research Clinical Trials Cocoa Powder Cognitive aging Consumption Data Dementia Development Diet Dietary Intervention Dietary intake Diffusion Elderly Endothelial Cells Endothelium Endotoxemia Epidemic Equipment Family Flavanol Food Functional Magnetic Resonance Imaging Functional disorder Goals HMGB1 gene Health Healthcare Systems Hippocampus (Brain)Human Immune Impaired cognition Impairment Individual Inflammation Inflammation Mediators Inflammatory Innate Immune System Intake Intervention Investigation Learning Link Measurable Measures Mediating Mediation Mediator of activation protein Memory Memory impairment Methodology Microglia Modeling Nerve Degeneration Neurodegenerative Disorders Operative Surgical Procedures Oral Oxidative Stress Parkinson Disease Participant Pathology Pathway interactions Patients Peripheral Peripheral Nerves Pilot Projects Placebos Plants Plasma Population Production Quality of life Randomized Controlled Trials Recording of previous events Reporting Research Rodent Rodent Model Role Sentinel Serological Serum Signal Pathway Signal Transduction Structure Synaptic plasticity TLR4 gene TNF gene Testing Trauma Validation Variant Vasomotor age group age related base bean brain cell brain dysfunction cerebral blood volume cognitive function cytokine dentate gyrus dietary supplements epicatechin functional status glymphatic system group intervention human old age (65+)imaging approach improved improved functioning inflammatory marker insulin sensitivity macrophage neurogenesis neuroinflammation neuronal survival neuropathology nonhuman primate nutritional supplementation post intervention prevent primary outcome programs prospective septic patients stem cells therapeutic target vascular inflammation

项目摘要

Within 25 years, the US population aged 65 and over will double in size to 80 million bringing, with it an epidemic of aging-related cognitive decline, from normal cognitive aging to neurodegenerative disorders including Alzheimer’s Disease (AD). These conditions impair quality of life and functional status, impose an enormous burden on individuals, their families, the healthcare system, and require elucidation of mechanisms and development of new treatments to prevent or at least slow their progression. The use of plant-based food and drink for health purposes has a long and well-documented history. Cocoa beans contain the flavanol epicatechin, an anti-oxidant with beneficial effects on blood pressure, endothelium- dependent vasomotor function, platelet reactivity, insulin sensitivity, vascular inflammation, and circulating progenitor cells. Importantly, flavanols have neuroprotective effects, suppressing oxidative stress and inflammation and promoting neurogenesis, neuronal survival and synaptic plasticity, all of which are relevant to the pathophysiology of neurodegenerative disorders like AD, amyotrophic lateral sclerosis (ALS), and Parkinson’s Disease (PD). Evidence from humans, non-human primates, and rodents points to a role for the hippocampus and its subregions in aging-related neurodegenerative disorders including AD. We recently reported that dietary intake of cocoa flavanols increased hippocampal function, measured as fMRI cerebral blood volume (CBV) and a pilot mediation analysis showed that cocoa flavanols led to a decrease in the sentinel pro-inflammatory mediator HMGB1, an activator of the innate immune system. In turn, this decrease in HMGB1 was linked to improved hippocampal function. Recent evidence implicates HMGB1 in cognitive decline and impairment. HMGB1 binds to Toll-like receptor 4 (TLR4), triggering the production of pro-inflammatory cytokines including TNFa via NFkB-dependent pathways. In rodent models of endotoxemia and surgical trauma, HMGB1 mediated hippocampal-dependent memory impairment similar to that seen in septic patients, an effect eliminated by neutralizing HMGB1. These data mechanistically link HMGB1 to neurodegenerative impairment, suggesting its potential as a therapeutic target, consistent with evidence that amplified systemic inflammation is associated with a variety of age-related pathologies including Alzheimer’s Disease. They strongly support our major hypothesis that cocoa flavanols improve hippocampal function by their effects on neuroinflammation, specifically HMGB1, via a TLR4-NFkB-TNFa signaling pathway. We propose to test this model in a randomized controlled trial of 146 participants, age 50-69, receiving high or low daily cocoa flavanol for 12 weeks. Such a trial has potential for significant clinical impact.

25 年内，美国 65 岁及以上人口将翻一番，达到 8000 万，与衰老相关的认知能力下降的流行，从正常的认知衰老到神经退行性疾病包括阿尔茨海默病 (AD)，这些疾病会影响生活质量和功能状态。对个人、其家庭、医疗保健系统造成巨大负担，需要阐明机制以及开发新的治疗方法以预防或至少减缓其进展。将植物性食品和饮料用于健康目的有着悠久且有据可查的历史。豆类含有黄烷醇表儿茶素，这是一种抗氧化剂，对血压、内皮细胞有益依赖性血管舒缩功能、血小板反应性、胰岛素敏感性、血管炎症和循环重要的是，黄烷醇具有神经保护作用，抑制氧化应激和炎症并促进神经发生、神经元存活和突触可塑性，所有这些都与 AD、肌萎缩侧索硬化症 (ALS) 等神经退行性疾病的病理生理学帕金森病（PD）。来自人类、非人类灵长类动物和啮齿动物的证据表明海马体及其我们最近报道了与衰老相关的神经退行性疾病（包括 AD）的亚区域。摄入可可黄烷醇会增加海马功能，通过功能磁共振成像脑血容量（CBV）和初步中介分析表明，可可黄烷醇导致前哨促炎细胞减少 HMGB1 是先天免疫系统的激活剂，而 HMGB1 的减少又与此相关。改善海马功能。最近的证据表明 HMGB1 与认知能力下降和障碍有关。 HMGB1 与 Toll 样受体 4 (TLR4) 结合，触发促炎细胞因子的产生，包括在内毒素血症和手术创伤的啮齿动物模型中，HMGB1 通过 NFkB 依赖性途径发挥作用。介导的海马依赖性记忆障碍与脓毒症患者中观察到的相似，这是一种效应通过中和 HMGB1 来消除。这些数据将 HMGB1 与神经退行性损伤机械地联系起来，表明它作为一种药物的潜力治疗目标，与放大的全身炎症与多种疾病相关的证据一致它们强烈支持我们的主要假设：可可。黄烷醇通过对神经炎症（特别是 HMGB1）的影响来改善海马功能我们建议在一项包含 146 名受试者的随机对照试验中测试该模型。年龄 50-69 岁的参与者每天接受高或低的可可黄烷醇，持续 12 周。显着的临床影响。